COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

Malone, Robert E.; Tisdall, Philip; Fremont-Smith, Philip; Liu, Yongfeng; Huang, Xi‐Ping; White, Kris M.; Miorin, Lisa; Moreno, Elena; Alon, Assaf; Delaforge, Elise; Hennecker, Christopher; Wang, Guanyu; Pottel, Joshua; Bona, Robert; Smith, Nora; Hall, Julie M.; Shapiro, Gideon; Clark, Howard; Mittermaier, Anthony; Kruse, Andrew C.; Garcı́a-Sastre, Adolfo; Roth, Bryan L.; Glasspool-Malone, Jill; Francone, Victor; Hertzog, Norbert; Fremont‐Smith, Maurice; Ricke, Darrell O.

doi:10.21203/rs.3.rs-30934/v1

Cited by 10 publications

(8 citation statements)

References 59 publications

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“…Administration of the H-2 blocker famotidine to patients hospitalized with COVID-19, but not initially in the ICU, was associated with a twofold reduction in clinical deterioration leading to intubation or death [158]. Computational modeling indicated that famotidine directly binds and inhibits the SARS-CoV-2 processing enzyme NSP5 [158], but this drug lacked a direct anti-SARS-CoV-2 effect in vitro in Vero cells, and H-2-mediated antiviral effect is suggested [159]. In vitro, histamine pretreatment of C57BL/ 6 mouse splenocytes enhances STAT1 phosphorylation, and an H-2 antagonist (but not an H-1 antagonist) can augment STAT1 phosphorylation to a similar extent [160].…”

Section: Histamine Receptor-2 Blocker (H-2 Blocker)mentioning

confidence: 99%

An aberrant STAT pathway is central to COVID-19

Matsuyama

Kubli

Yoshinaga³

et al. 2020

Cell Death Differ

263

275

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COVID-19 is caused by SARS-CoV-2 infection and characterized by diverse clinical symptoms. Type I interferon (IFN-I) production is impaired and severe cases lead to ARDS and widespread coagulopathy. We propose that COVID-19 pathophysiology is initiated by SARS-CoV-2 gene products, the NSP1 and ORF6 proteins, leading to a catastrophic cascade of failures. These viral components induce signal transducer and activator of transcription 1 (STAT1) dysfunction and compensatory hyperactivation of STAT3. In SARS-CoV-2-infected cells, a positive feedback loop established between STAT3 and plasminogen activator inhibitor-1 (PAI-1) may lead to an escalating cycle of activation in common with the interdependent signaling networks affected in COVID-19. Specifically, PAI-1 upregulation leads to coagulopathy characterized by intravascular thrombi. Overproduced PAI-1 binds to TLR4 on macrophages, inducing the secretion of proinflammatory cytokines and chemokines. The recruitment and subsequent activation of innate immune cells within an infected lung drives the destruction of lung architecture, which leads to the infection of regional endothelial cells and produces a hypoxic environment that further stimulates PAI-1 production. Acute lung injury also activates EGFR and leads to the phosphorylation of STAT3. COVID-19 patients' autopsies frequently exhibit diffuse alveolar damage (DAD) and increased hyaluronan (HA) production which also leads to higher levels of PAI-1. COVID-19 risk factors are consistent with this scenario, as PAI-1 levels are increased in hypertension, obesity, diabetes, cardiovascular diseases, and old age. We discuss the possibility of using various approved drugs, or drugs currently in clinical development, to treat COVID-19. This perspective suggests to enhance STAT1 activity and/or inhibit STAT3 functions for COVID-19 treatment. This might derail the escalating STAT3/PAI-1 cycle central to COVID-19.

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Section: Histamine Receptor-2 Blocker (H-2 Blocker)mentioning

confidence: 99%

An aberrant STAT pathway is central to COVID-19

Matsuyama

Kubli

Yoshinaga³

et al. 2020

Cell Death Differ

263

275

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“…Elevated PGE 2 may be driving hyper-activation of mast cells associated with excess release of histamine and additional inflammatory molecules (5). COVID-19 is predicted to be a mast cell disease (6).…”

Section: Introductionmentioning

confidence: 99%

Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies

Ricke

2021

Front. Immunol.

Self Cite

120

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COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.

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“…These data suggest that addition of broad spectrum pharmaceutical immunosuppression using corticosteroids must indeed be "compared with other antiin ammatory drugs", and that the targeted famcox antihistamine/COX-2 anti-in ammatory strategy should not be combined with potent broad spectrum, non-speci c immunosuppression when treating COVID-19. However, conclusive analysis of this preliminary observation will require larger prospective This study builds upon previously published original research, a case report, and a case series report concerning use of High Dose famotidine for COVID-19 treatment (Janowitz et al, 2020;Malone et al, 2021), a prospective randomized controlled trial of celecoxib for COVID-19 treatment (Hong et al, 2020), and a detailed case series and reports involving COVID-19 treatment with the combination of High Dose famotidine + celecoxib 2021). A key weakness in this comparative consecutive cohort analysis is that this study design is not able to control for all factors (known, unknown and unknowable) that differ between the two cohorts at the point of enrollment into the study, and so is subject to uncontrolled confounding during group selection.…”

Section: Discussionmentioning

confidence: 92%

“…Building on our initial discovery of the activity and mechanism of action of the histamine H2 receptor inverse agonist famotidine for reducing COVID-19 symptoms (Malone, 2021;Malone et al, 2021), we have combined this agent with the COX-2 inhibitor celecoxib (Baghaki et al, 2020;Hong et al, 2020) to produce a binary treatment protocol (Tomera et al, 2021). This yielded an adjuvant anti-in ammatory combination with speci c and well-characterized MOA which appears to provide potent clinical responses in hospitalized COVID-19 patients (Tomera et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Both of these agents are off-patent, generic, inexpensive, widely available, have been administered for many years to many patients, and have extensive safety and drug-interaction databases. MOA, dosing and safety considerations for these agents when used to treat COVID-19 have been investigated and discussed in preceding publications (Hong et al, 2020;KM Tomera, 2020;Malone et al, 2021;Tomera et al, 2021). In brief, one working hypothesis is that viral activation of COX-2 expression in infected cells (Chen et al, 2021) (mediated by SARS-CoV-2 spike and nucleocapsid proteins (Yan et al, 2006;Liu et al, 2007)) drives production of elevated Prostaglandin E2 (PGE2) and related signaling molecules, mast cell/basophil recruitment and degranulation, and a self-reinforcing positive feedback loop with some features of mast cell activation syndrome.…”

Section: Discussionmentioning

confidence: 99%

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Famotidine and Celecoxib COVID-19 Treatment Without and With Dexamethasone; Retrospective Comparison of Sequential Continuous Cohorts

Malone

Tomera

Egbujiobi

et al. 2021

Preprint

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We seek to rapidly identify, test and develop combinations of repurposed drugs to enable cost-effective treatments that reduce the risk of disease or death from SARS-CoV-2 infection. We hypothesize that the morbidity and mortality of COVID-19 reflects overactive host inflammatory responses to infection and is not principally due to the primary direct cellular, organ and tissue damage attributable to viral infection. Stepwise clinical development has identified the combination of High Dose (HD) famotidine and celecoxib (famcox) as a promising adjuvant anti-inflammatory protocol. We now report results from a retrospective observational comparative cohort study designed to provide an estimate of the potential benefits, risks, prognosis and diagnostic laboratory findings associated with administration of dexamethasone in addition to famcox for treatment of newly hospitalized COVID-19 disease in a community hospital setting. Study enrollment was restricted to patients at WHO 4–5. In the group receiving adjuvant treatment with famcox without dexamethasone (active control) there were no deaths during hospitalization (0/18 = 0% mortality). A total of six deaths occurred in the group receiving famcox + dexamethasone (6/21 = 29% mortality). There was a significant difference in mortality between the two groups, Χ2 (1, N = 43) = 7.305, p < 0.007. Median time to event for reaching WHO score of < 4 was 3.5 days in the control group (famcox (–) dex) versus 10 days for the experimental group (famcox (+) dex) P < 0.001. We conclude that use of the potent non-specific anti-inflammatory corticosteroid dexamethasone in addition to the specific anti-inflammatory famcox protocol should only be considered in late stage COVID-19 disease in patients less than 70 years of age. The effects of added dexamethasone on laboratory biomarkers, and particularly on neutrophil count, lymphocyte count, and neutrophil to lymphocyte ratio raise concerns about the long-term effects of dexamethasone treatment with or without famcox during acute COVID-19 on the incidence and severity of chronic COVID (“long COVID” or PASC).

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COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

Cited by 10 publications

References 59 publications

An aberrant STAT pathway is central to COVID-19

An aberrant STAT pathway is central to COVID-19

Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies

Famotidine and Celecoxib COVID-19 Treatment Without and With Dexamethasone; Retrospective Comparison of Sequential Continuous Cohorts

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